Phospho-HDAC6 Gathers Into Protein Aggregates in Parkinson's Disease and Atypical Parkinsonisms.

HDAC6 is a unique histone deacetylase that targets cytoplasmic non-histone proteins and has a specific ubiquitin-binding activity. Both of these activities are required for HDAC6-mediated formation of aggresomes, which contain misfolded proteins that will ultimately be degraded via autophagy. HDAC6 deacetylase activity is increased following phosphorylation on serine 22 (phospho-HDAC6). In human, HDAC6 localizes in neuronal Lewy bodies in Parkinson's disease (PD) and in oligodendrocytic Papp-Lantos bodies in multiple system atrophy (MSA). However, the expression of phospho-HDAC6 in post-mortem human brains is currently unexplored. Here, we evaluate and compare the distribution of HDAC6 and its phosphorylated form in human brains obtained from patients affected by three forms of parkinsonism: two synucleinopathies (PD and MSA) and a tauopathy (progressive supranuclear palsy, PSP). We find that both HDAC6 and its phosphorylated form localize with pathological protein aggregates, including α-synuclein-positive Lewy bodies in PD and Papp-Lantos bodies in MSA, and phospho-tau-positive neurofibrillary tangles in PSP. We further find a direct interaction of HDAC6 with α-synuclein with proximity ligation assay (PLA) in neuronal cell of PD patients. Taken together, our findings suggest that both HDAC6 and phospho-HDAC6 regulate the homeostasis of intra-neuronal proteins in parkinsonism.

Alzheimer neuropathology without frontotemporal lobar degeneration hallmarks (TAR DNA-binding protein 43 inclusions) in missense progranulin mutation Cys139Arg.

Null mutations in progranulin gene (GRN) reduce the progranulin production resulting in haploinsufficiency and are tightly associated with tau-negative frontotemporal lobar degeneration with TAR DNA-binding protein 43-positive inclusions (FTLD-TDP). Missense mutations of GRN were also identified, but their effects are not completely clear, in particular unanswered is the question of what neuropathology they elicit, also considering that their occurrence has been reported in patients with typical clinical features of Alzheimer disease. They describe two fraternal twins carrying the missense GRN Cys139Arg mutation affected by late-onset dementia and we report the neuropathological study of one of them. Both patients were examined by neuroimaging, neuropsychological assessment and genetic analysis of GRN and other genes associated with dementia. The brain of one was obtained at autopsy and examined neuropathologically. One sister presented clinical and MRI features leading to the diagnosis of Alzheimer disease. The other underwent autopsy and the brain showed neuropathological hallmarks of Alzheimer disease with abundant Aß-amyloid deposition and Braak stage V of neurofibrillary pathology, in the absence of the hallmark lesions of FTLD-TDP. Their findings may contribute to better clarify the role of progranulin in neurodegenerative diseases indicating that some GRN mutations, in particular missense ones, may act as strong risk factor for Alzheimer disease rather than induce FTLD-TDP.

Measles Inclusion-Body Encephalitis: Neuronal Phosphorylated Tau Protein is Present in the Biopsy but not in the Autoptic Specimens of the Same Patient.

Tauopathies are sporadic or familial neurodegenerative diseases characterized by the accumulation of phosphorylated tau in neurons and glial cells and include encephalitis related to measles virus such as subacute sclerosing panencephalitis. We describe a 45-year-old woman, with a history of lymphoma treated with immunosuppressant therapy who underwent an open biopsy of the right frontal cortex for a suspect of encephalitis, and died 4 days later. The neuropathological assessment on the bioptic sample revealed edema, severe gliosis and microglial activation, with lymphomonocytic perivascular cuffing and neurons containing both nuclear and cytoplasmic eosinofilic inclusions that ultrastructurally appeared as tubular and curvilinear non-membrane-bound 12-18 nm structures, leading to the diagnosis of measles inclusion-bodies encephalitis. The biopsy specimen showed several cortical neurons with intense perikaryal immunoreactivity for anti-tau antibodies recognizing phosphorylated epitopes while on autoptic specimens no phosphorylated tau immunoreactivity was detected. Our findings suggest that in specific conditions biopsy-derived human tau may be phosphorylated at sites that may result not phosphorylated in autopsy-derived specimens, most likely caused by post-mortem dephosphorylation.